Rickets and Alopecia with Resistance to 1,25-Dihydroxyvitamin D: Two Different Clinical Courses with Two Different Cellular Defects*

Balsan, S; Garabédian, M; Liberman, Uri; Bourdeau, A.; Eil, Charles; Guillozo, H.; Grimberg, R; Deunff, M. J. Le; Lieberherr, Michèle; Guimbaud, P; Broyer, M.; Marx, Stephen J.

doi:10.1210/jcem-57-4-803

Cited by 86 publications

(34 citation statements)

References 28 publications

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“…It is also well established that 1,25(OH)2D3 stimulates osteocalcin synthesis (37), and 25(OH)D3-24 hydroxylase (38). Previou's studies on cultured fibroblasts from our patient showed abnormalities in cytosol binding and nuclear uptake of [3H]1,25(OH)2D3 (10 it must be via a mechanism that does not involve the hormone receptor-effector system. In effect, our data provide convincing evidence that, in humans, normal mineralization can be achieved even in the absence of a normal 1,25(0H)2D3 receptor-effector system, provided that normal circulating calcium and phosphorus concentrations are maintained.…”

Section: Discussionsupporting

confidence: 51%

“…The detailed case history of patient A up to the age of 8 yr, from November 1974 to May 1983, has been previously reported (10). This child, born in 1974 to consanguinous parents, had congenital alopecia, and indications of rickets were first seen on radiographs when she was aged 7 mo.…”

Section: Methodsmentioning

confidence: 95%

“…Whatever the basic molecular defect(s), the accumulating data clearly show a great heterogeneity in the clinical features ofpatients with hereditary resistance to 1,25(OH)2D and in their response to therapy with vitamin D derivatives (1). Favorable clinical responses to the administration ofpharmacological doses of native vitamin D, 25(OH)D3, la(OH)D3, 1,25(OH)2D3 (3)(4)(5)(6)(7)(8)(9)(10), or 24,25(OH)2D3 (11) have been reported in some patients. However, it has been shown that other patients with resistance to 1,25(0H)2D3 may remain unresponsive to similar therapeutic trials (10,12,13) or, after prolonged remission oftheir symptoms, become completely refractory to treatment with vitamin D derivatives (10).…”

Section: Introductionmentioning

confidence: 99%

“…Death during the first three years of life, mainly due to pulmonary complications or hypocalcemic convulsions, has been reported in six children belonging to three affected kindreds (10, 1 1). Dwarfism, skeletal deformities, myopathy, and bone pain may seriously handicap such patients (10,14).…”

Section: Introductionmentioning

confidence: 99%

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Long-term nocturnal calcium infusions can cure rickets and promote normal mineralization in hereditary resistance to 1,25-dihydroxyvitamin D.

Balsan¹,

Garabédian²,

Larchet³

et al. 1986

J. Clin. Invest.

253

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We report the beneficial effects of calcium infusions in a child with hereditary resistance to 1,25(OH)2D and alopecia. This patient after transient responsiveness to vitamin D derivatives became unresponsive to all therapy despite serum 1,25(OH)2D concentrations maintained at levels -100-fold normal. A 7-mo trial with calcium infusions led to correction of biochemical abnormalities and healing of rickets. Bone biopsies (n = 3) showed a normal mineralization and the disappearance of the osteomalacia. Cultures of bone-derived cells demonstrated a lack of activation of 25-hydroxyvitamin D 24-hydroxylase and osteocalcin synthesis by 1,25(0H)2D3 (10-' and 10' M). These results demonstrate that (a) even in the absence of a normal 1,25(OH)2D3 receptor-effector system in bone cells, normal mineralization can be achieved in humans if adequate serum calcium and phosphorus concentrations are maintained; and (b) calcium infusions may be an efficient alternative for the management of patients with this condition who are unresponsive to large doses of vitamin D derivatives.

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Section: Discussionsupporting

confidence: 51%

Section: Methodsmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Long-term nocturnal calcium infusions can cure rickets and promote normal mineralization in hereditary resistance to 1,25-dihydroxyvitamin D.

Balsan¹,

Garabédian²,

Larchet³

et al. 1986

J. Clin. Invest.

253

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“…Clinically, the syndrome is recognized by severe early onset rickets with bowing of the lower extremities, short stature, and often alopecia (2)(3)(4)(5). Resistance to 1,25D 3 in HVDRR leads to impaired intestinal calcium absorption.…”

Section: Hereditary Vitamin D-resistant Rickets (Hvdrr)mentioning

confidence: 99%

A Rationale for Treatment of Hereditary Vitamin D-resistant Rickets with Analogs of 1α,25-Dihydroxyvitamin D3

Gardezi¹,

Nguyen²,

Malloy³

et al. 2001

Journal of Biological Chemistry

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Hereditary vitamin D-resistant rickets (HVDRR) is caused by heterogeneous inactivating mutations in the vitamin D receptor (VDR). Treatment of HVDRR patientswith high doses of oral calcium and supraphysiologic doses of 1␣,25-dihydroxyvitamin D 3 (1,25D 3 ) has had limited success. In this study we explored the use of vitamin D analogs as a potential therapy for this disorder. The rationale for the use of vitamin D analogs is that they bind the VDR at different amino acid residues than 1,25D 3 , and their ability to modulate VDR functions differs from that of the natural hormone. In this report, we examined the VDR from three HVDRR patients with mutations in the ligand-binding domain of the VDR (histidine 305 to glutamine, arginine 274 to leucine, and phenylalanine 251 to cysteine) for their responses to two vitamin D analogs, 20-epi-1,25D 3 and 1␤-hydroxymethyl-3-epi-16-ene-26a,27a-bishomo-25D 3 (JK-1626-2). Our results reveal that vitamin D analogs partially or completely restore the responsiveness of the mutated VDR. Analog treatment seemed to be more successful when the mutation affects the amino acids directly involved in ligand binding rather than amino acids that contribute to a functional VDR interface with dimerization partners or coactivators of transcription. Hereditary vitamin D-resistant rickets (HVDRR)1 is an autosomal recessive disorder characterized by end-organ resistance to 1␣,25-dihydroxyvitamin D 3 (1,25D 3 ) (1, 2). Clinically, the syndrome is recognized by severe early onset rickets with bowing of the lower extremities, short stature, and often alopecia (2-5). Resistance to 1,25D 3 in HVDRR leads to impaired intestinal calcium absorption. This results in a series of metabolic abnormalities including frank hypocalcemia, secondary hyperparathyroidism, elevated alkaline phosphatase levels, hypophosphatemia, and markedly increased 1,25D 3 levels (2). Treatment of HVDRR patients with high doses of oral calcium and supraphysiologic doses of 1,25D 3 has had limited success. More aggressive therapy to bypass the defect in intestinal calcium absorption is long term intravenous infusion of calcium that restores the serum calcium levels to normal and reverses the rickets in some cases (2, 5-7). However, this approach has the usual complications associated with intravenous therapy, and its use has been limited because of its complexity.The resistance to 1,25D 3 in HVDRR is caused by heterogeneous mutations in the nuclear receptor for vitamin D (2, 8, 9). Therefore, this disease emphasizes the importance of vitamin D receptor (VDR)-mediated action of 1,25D 3 in skeletal development and bone mineralization as well as in the development of hair follicles. Like other members of the nuclear receptor superfamily, the VDR is activated by binding to its ligand (1,25D 3 ), and its action is mediated through distinct functional domains for DNA binding, ligand binding, and transcriptional activation (10, 11). HVDRR patients with mutations in the DNA binding domain of VDR do not respond to 1,25D 3 treatment mainly...

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Rickets and Osteomalacia

Yamanaka¹,

Seino²

2002

Calcium in Internal Medicine

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Rickets and Alopecia with Resistance to 1,25-Dihydroxyvitamin D: Two Different Clinical Courses with Two Different Cellular Defects*

Cited by 86 publications

References 28 publications

Long-term nocturnal calcium infusions can cure rickets and promote normal mineralization in hereditary resistance to 1,25-dihydroxyvitamin D.

Long-term nocturnal calcium infusions can cure rickets and promote normal mineralization in hereditary resistance to 1,25-dihydroxyvitamin D.

A Rationale for Treatment of Hereditary Vitamin D-resistant Rickets with Analogs of 1α,25-Dihydroxyvitamin D3

Rickets and Osteomalacia

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